Numerous studies implicate a critical role of the nucleus accumbens (NAc) and its dopaminergic input in goal-directed behavior for cocaine and 'natural' (e.g., food/water) rewards. The PI has used electrophysiological recording procedures in behaving rats to investigate underlying cellular mechanisms mediating reward-seeking behavior. To examine the role of dopamine (DA) in this process, fast scan cyclic voltammetry (FSCV) was used, a technique that allows direct measurement of DA in the NAc on a subsecond time scale with micron spatial resolution. Thus, FSCV provides chemical information temporally analogous to data obtained from electrophysiology. Working with R. Mark Wightman, changes in DA efflux were uncovered in the NAc during key aspects of reward-seeking involving natural rewards (e.g., sucrose), intracranial self-stimulation (ICSS) and cocaine self-administration. In order to make definitive statements about the relationship between specific types of cellular discharges and DA, this grant was originally submitted as a Cutting Edge Basic Research Award to develop and apply the technology to measure changes in NAc cell firing and NAc DA from the same electrode in behaving rats. This combined approach enabled the first unique view of real-time, spatially resolved concentration fluctuations of DA in conjunction with changes in cell firing during behavior. In the last funding period key factors were determined that control rapid DA signaling (using FSCV alone) and its relationship to NAc cell firing during behavior (using the combined technique). Here, 4 specific aims are proposed to build upon that work. Aim1 will use FSCV alone to determine if rapid DA release is altered during a cocaine/sucrose multiple schedule when animals switch from responding for one versus the other reward. Thus, we will determine if DA release within specific locations occurs uniformly during operant responding for both rewards, or if distinct subregions exist in the NAc at which DA release selectively occurs depending upon reinforcer type. Aim 2 will build upon prior work by the PI and determine the effects of interruption of drug access (cocaine abstinence) on rapid DA signaling in the NAc. Our prior electrophysiology studies revealed a heightened activation of NAc cell firing following 1-month cocaine abstinence. Here, we will incorporate drug abstinence and reinstatement procedures to determine if interruption of cocaine self-administration enhances rapid DA release during subsequent cocaine-seeking behavior. Although the NAc is clearly linked with reward, less is known about its role in aversion. Aim 3 will use the combined voltammetry/electrophysiology technique to determine the precise relationship between rapid DA signaling and NAc cell firing during intra-oral infusions of a rewarding (sucrose) vs. aversive (quinine) tastant. Aim 4 will expand that study and apply our improved iontophoresis method in conjunction with the combined voltammetry/electrophysiology technology to determine potential causal links between rapid DA signaling and NAc cell firing during rewarding and aversive situations. PUBLIC HEALTH RELEVANCE: Cocaine addiction is a serious problem in the United States, yet strategies to treat cocaine abuse are limited. The significance of this research is that it will provide unprecedented information regarding the actions of rewarding (e.g., cocaine) and aversive substances on dopamine release and the activity of brain cells in the nucleus accumbens (NAc), a brain structure known to be crucially involved in mediating the reinforcing actions of abused substances. The information obtained from the present application will provide insight into the neurobiological mechanisms mediating cocaine addiction and thereby aid in the development of pharmacological agents to treat human drug addiction.